Synthesis, Characterization, Cytotoxicity, Cellular Imaging, Molecular Docking, and ADMET Studies of Piperazine-Linked 1,8-Naphthalimide-Arylsulfonyl Derivatives
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis and Characterization
2.2. Optical Studies
2.3. Biological Studies
2.3.1. Cytotoxicity
2.3.2. Fluorescence Imaging
2.4. Computational Studies
2.4.1. Molecular Docking
2.4.2. Molecular Dynamics (MD) Simulation
2.4.3. Molecular Mechanics Poisson–Boltzmann Surface Area (MM/PBSA)
2.4.4. Drug Likeness and Bioavailability Studies
2.4.5. Toxicological Prediction
3. Materials and Methods
3.1. General Protocol for the Synthesis
3.2. Biological Studies
3.2.1. Cytotoxicity Assay
3.2.2. Fluorescence Imaging Assay
3.3. Computational Details
3.3.1. Docking (Ligands, Receptor, and Grid Preparation)
3.3.2. Molecular Dynamics (MD) Simulation
3.3.3. Absorption, Distribution, Metabolism, and Excretion and Toxicity (ADMET) Studies
3.3.4. Determining Binding Free Energy
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Sample | Absorption (λmax. nm) | Emission (λem. nm) 1 | Stokes Shift (nm) 1 | Quantum Yield (Φ) | |
---|---|---|---|---|---|
DCM | DMSO | ||||
SA1 | 238, 333, 348 | 259, 336, 351 | 401 | 50 | 0.030 |
SA2 | 240, 333, 348 | 261, 327, 336 | 401 | 65 | 0.071 |
SA3 | 236, 333, 349 | 261, 336, 350 | 401 | 51 | 0.048 |
SA4 | 238, 333, 348 | 260, 336, 352 | 401 | 49 | 0.042 |
SA5 | 238, 334, 348 | 260, 336, 352 | 402 | 50 | 0.035 |
SA6 | 236, 333, 349 | 260, 336, 352 | 401 | 49 | 0.033 |
SA7 | 239, 333, 348 | 260, 336, 351 | 401 | 50 | 0.041 |
Code | Docking Results | Molecular and ADME Properties | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Binding Affinity (kcal/mol) | No. of Amino Acids Involved in H-Bonding | CNS | MW | Dipole Moment | SASA | FOSA | FISA | PISA | WPSA | Volume | HBD | HBA | |
SA1 | −7.39 | 4 | −2 | 494.52 | 8.90 | 730.17 | 162.83 | 186.15 | 381.02 | 0.155 | 1374.89 | 0 | 10.5 |
SA2 | −8.39 | 3 | 1 | 499.58 | 3.00 | 785.48 | 169.23 | 118.06 | 497.58 | 0.599 | 1457.18 | 0 | 9.5 |
SA3 | −7.92 | 5 | −2 | 494.52 | 5.97 | 752.79 | 168.74 | 223.12 | 360.29 | 0.644 | 1389.51 | 0 | 10.5 |
SA4 | −8.04 | 4 | 1 | 489.99 | 7.90 | 730.25 | 168.54 | 129.12 | 319.80 | 112.773 | 1337.84 | 0 | 9.5 |
SA5 | −7.95 | 4 | 1 | 455.55 | 8.28 | 704.55 | 168.57 | 129.16 | 364.64 | 42.176 | 1292.57 | 0 | 9.5 |
SA6 | −7.65 | 2 | 0 | 450.51 | 6.15 | 709.72 | 169.15 | 153.91 | 386.03 | 0.621 | 1305.80 | 0 | 11 |
SA7 | −8.61 | 4 | −2 | 474.53 | 5.76 | 751.89 | 168.66 | 197.45 | 385.18 | 0.6 | 1381.68 | 0 | 11 |
Code | Protein RMSD (nm) | SD | Ligand RMSD (nm) | SD | RMSF (nm) | SD | MM/PBSA (kJ/mol) |
---|---|---|---|---|---|---|---|
SA2 | 1.57 | 0.16 | 1.82 | 0.46 | 0.81 | 0.35 | −36.78 |
SA4 | 1.71 | 0.26 | 1.40 | 0.25 | 0.82 | 0.45 | −37.93 |
SA5 | 1.63 | 0.25 | 1.66 | 0.29 | 0.84 | 0.47 | −36.61 |
SA7 | 1.47 | 0.14 | 1.85 | 0.20 | 0.81 | 0.38 | −28.21 |
Comp. Code | TPSA | Mol. Wt. | logP | # RBs | |
---|---|---|---|---|---|
SA1 | 133.9 | 1.95 | 6 | ||
SA2 | 88.1 | 3.63 | 5 | ||
SA3 | 133.9 | 2.03 | 6 | ||
SA4 | 116.3 | 3.41 | 5 | ||
SA5 | 116.3 | 2.81 | 5 | ||
SA6 | 101.0 | 2.02 | 5 | ||
SA7 | 111.9 | 2.53 | 5 |
Parameters | SA1 | SA2 | SA3 | SA4 | SA5 | SA6 | SA7 |
AMES toxicity | Yes | Yes | Yes | Yes | Yes | No | Yes |
Max. tolerated dose | −0.284 | 0.102 | −0.233 | −0.135 | −0.171 | −0.129 | −0.184 |
hERG I inhibitor | No | Yes | No | No | No | No | No |
hERG II inhibitor | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
Oral rat acute tox. (LD50) | 2.97 | 2.179 | 2.965 | 2.664 | 2.562 | 2.643 | 2.541 |
Chronic oral rat tox. (LOAEL) | 1.934 | 1.37 | 2.026 | 1.309 | 1.382 | 0.435 | 1.331 |
Hepatotoxicity | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
Skin sensitization | No | No | No | No | No | No | No |
T. Pryiformis toxicity | 0.291 | 0.286 | 0.292 | 0.32 | 0.323 | 0.302 | 0.31 |
Minnow toxicity | 1.591 | 0.954 | 1.314 | 0.5 | 0.858 | −0.044 | 0.869 |
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Haque, A.; Alenezi, K.M.; Al-Otaibi, A.; Alsukaibi, A.K.D.; Rahman, A.; Hsieh, M.-F.; Tseng, M.-W.; Wong, W.-Y. Synthesis, Characterization, Cytotoxicity, Cellular Imaging, Molecular Docking, and ADMET Studies of Piperazine-Linked 1,8-Naphthalimide-Arylsulfonyl Derivatives. Int. J. Mol. Sci. 2024, 25, 1069. https://doi.org/10.3390/ijms25021069
Haque A, Alenezi KM, Al-Otaibi A, Alsukaibi AKD, Rahman A, Hsieh M-F, Tseng M-W, Wong W-Y. Synthesis, Characterization, Cytotoxicity, Cellular Imaging, Molecular Docking, and ADMET Studies of Piperazine-Linked 1,8-Naphthalimide-Arylsulfonyl Derivatives. International Journal of Molecular Sciences. 2024; 25(2):1069. https://doi.org/10.3390/ijms25021069
Chicago/Turabian StyleHaque, Ashanul, Khalaf M. Alenezi, Ahmed Al-Otaibi, Abdulmohsen Khalaf Dhahi Alsukaibi, Ataur Rahman, Ming-Fa Hsieh, Mei-Wen Tseng, and Wai-Yeung Wong. 2024. "Synthesis, Characterization, Cytotoxicity, Cellular Imaging, Molecular Docking, and ADMET Studies of Piperazine-Linked 1,8-Naphthalimide-Arylsulfonyl Derivatives" International Journal of Molecular Sciences 25, no. 2: 1069. https://doi.org/10.3390/ijms25021069